This application is a 371 of PCT/HU00/00081, filed Jul. 13, 2000
Spiro[(4-cyclohexanone)-[3H]indol-2xe2x80x2[1xe2x80x2H]-one and dispiro[(1,3-dioxolan)-2,-4xe2x80x2-cyclohexane-3H]indol]-2xe2x80x3[1xe2x80x3H]-one derivatives are important intermediates to the vasopressine V2 antagonistic compound, SR 121463. For example, as described in patent application WO 9715556 the dispiro[(1,3-dioxolan)-2,4xe2x80x2-cyclohexane-1,-3xe2x80x3-(5xe2x80x3-ethoxy)-[3H]indol]-2xe2x80x3[1xe2x80x3H]-one (compound of formula VII) 
can be prepared by reacting 4-ethoxyphenylhydrazine with 4-(1, 3-dioxolan)cyclohexane-carboxylate sodium salt followed by cyclization of the resulting 1-(4xe2x80x2-ethoxyphenyl)-2-(4xe2x80x3-/1,3-dioxolan/-cyclohexane-carbonyl)-hydrazine.
According to another synthetic route (EP 636608) the compound of formula VII is obtained by oxidation of the spiro[(4-hydroxy-cyclohexane)-1,3xe2x80x2(5xe2x80x2-ethoxy)-[3H]indol-2xe2x80x2[1xe2x80x2H]-one to the appropriate cyclohexanone derivative, from which the ketal of the formula VII is prepared by reaction with ethylene glycol.
Disadvantages of both of the above syntheses are the toxic starting materials, many-step syntheses, low yields of some synthetic steps, expensive reagents and extreme reaction conditions in certain reactions.
To our surprise, we have found that in contrast to the analogous reaction described in the literature (Annalen 1941, 548, 117-146; J. Am. Chem. Soc. 1953, 75, 5301-5305; J. Chem. Soc. C, 1970, 796-800, J. Med. Chem. 1993, 36, 2459-2469) the addition of methyl or ethyl acrylate to 5-ethoxy-indolinone, followed by Dieckmann-condensation, hydrolysis and decarboxylation does not lead to a homogeneous product, that is why the procedures described in the literature above are not suitable for industrial synthesis. We have found that the hydrogen in position-1 of the 5-ethoxy-indolinone has to be substituted by an appropriate protective group, if we want the subsequent reactions to proceed in the desired direction.
In the case the substituent in position-1 is a phenyl group as described in U.S. Pat. No. 3,395,156 side reactions cannot be avoided. Before the Dieckmann-condensation the obtained 1-phenyloxindole-3,3-dipropionic acid ester has to be hydrolyzed and reesterified to get a pure starting material.
The subject of our invention is a process for the preparation of spiro [(4-cyclohexanone)-[3H]indol]-2xe2x80x2[1xe2x80x2H]-one derivatives of the general formula I 
xe2x80x94wherein R1 and R2 independently stand for hydrogen, C1-4alkyl, C1-4alkoxy, C1-4altkylthio, C1-4polyfluoroalky, C1-4polyfluorbalkoxy, C3-7cycloakyloxy, C3-7cycloalkylthio, phenoxy, benzyloxy or nitro groupxe2x80x94,
characterized by reacting an indolin-2-one derivative of the general formula II 
xe2x80x94wherein R1 and R2 are as defined abovexe2x80x94with a compound capable for introducing a protective group, selected from 2-tetrahydropyranyl, 1-diethoxy-methylene or C1-4alkoxycarbonylethyl group, coupling the compound of general formula III, 
thus obtainedxe2x80x94wherein R1 and R2 are as defined above and A stands for a protective group, selected from 2-tetrahydropyranyl, 1-diethoxy-methylene or C1-4alkoxycarbonylethyl groupxe2x80x94with an acrylic acid C1-4ester, cyclizing the resulting compound of the general formula IV 
xe2x80x94wherein R1, R2 and A are as defined above, R3 stands for C1-4 alkyl groupxe2x80x94, eliminating the xe2x80x94COOR3 group and the A protective group of the keto-ester of general formula V 
xe2x80x94wherein R1, R2, R3 and A are as defined above, optionally without isolation of the compounds of the general formulae IV 
As for compounds capable to introduce the A protective group 2,3-dihydropyrane, triethyl orthoformate or an acrylic acid C1-4ester can be applied.
The reaction of the compound of general formula II 
xe2x80x94wherein R1 and R2 are as defined abovexe2x80x94with the compound capable to introduce the A protective group is preferably carried out in the presence of a catalyst, preferably in the presence of ptoluenestilfonic acid. As for solvent halogenated hydrocarbons, preferably dichioromethane can be used.
The reaction of the compounds of general formulae II 
xe2x80x94wherein R1, R2 and A are as defined abovexe2x80x94with the acrylic acid C1-4ester is carried out in the presence of a catalyst, preferably in the presence of an alkali alcoholate, favorably sodium alcoholate.
Cyclization of the compounds of general formula IV 
is carried out in the presence of an alkali alcoholate, preferably in the presence of sodium ethylate, potassium t-butylate.
Using acrylic acid C1-4ester for protective group, the process can advantageously performed as a xe2x80x9cone potxe2x80x9d method, in a polar solvent, in the presence of a base.
Compounds of the general formulae III, 
xe2x80x94wherein R1,R2,R3 and A are as defined abovexe2x80x94are new compounds, with the proviso, that in compound IV, if R1 and R2 stand for hydrogen, A is different from methoxycarbonyl-ethyl group.